Targeting leptin's signalling axis to prevent treatment resistance in prostate cancer

Overview

Advanced prostate cancer (PCa) is a leading cause of cancer-associated death in Australian men. Anti-androgens, which exploit the tumour’s reliance on androgens for its growth & spread, offer temporary remission in advanced PCa patients, but due to treatment resistance, fail to be curative. A further complication of anti-androgens is that they trigger a deleterious suite of metabolic side-effects resembling obesity/Metabolic syndrome. These symptoms not only impact patient health but promote tumours to be more aggressive & resist treatment. Vital new treatments are therefore required.

Leptin is fat-secreted hormone known for its role in obesity, metabolism & hunger; but its circulating levels are also dramatically increased in men with PCa & further increased in men with advanced disease. Our work uncovered that leptin’s signalling receptor is also increased in prostate tumour tissue, is again further increased in metastatic PCa & is linked to treatment resistance. We therefore developed a completely novel treatment strategy, inhibiting the leptin signalling axis, to halt PCa progression. Using a potent peptide drug to antagonise leptin signalling, we demonstrated leptin receptor blockade successfully inhibits prostate tumour growth, regressed tumours, slows progression to treatment resistance & extends mouse survival.

This project aims to determine our novel leptin receptor antagonist drug’s impact in preclinical models of PCa by: (1) assessing its anti-tumour efficacy, (2) characterising efficacious response in tumours by assessing drug impacts on key cancer hallmarks, & (3) characterising whole-body metabolic response to drug. These objectives are expected to contribute to our industry-partnered development of this novel drug and its future progression to clinical testing.

This project may employ multiple preclinical and molecular techniques to best understand the impact of our novel drug on whole-body phenotype and anti-tumour efficacy. Approaches used could include:

• animal modelling of prostate cancer for preclinical drug testing
• metabolic phenotyping & body composition imaging of mice
• characterisation of tumours in live animals by imaging techniques
• characterisation of drug impacts on tissues through standard molecular techniques (qRT-PCR, Western blot, ELISA, Immunohistochemistry), & multi-omics techniques with subsequent bioinformatic analysis.

Through this project, prospective students will gain skills in numerous scientific techniques that are broadly applicable throughout the biomedical science disciplines. Based at the world-class Translational Research Institute, the student(s) will access the state-of-the-art facilities and join a vibrant team of talented biomedical researchers within the Adipokine research group and broader Australian Prostate Cancer Research Centre – Queensland.

Keywords

• Adipokines
• Prostate Cancer
• Treatment Resistance
• Adiponectin
• Leptin
• Novel Drugs
• Preclinical Models

Contact

Contact Lisa Philp for more information.